The Story of BRAF

GENE STORY

The Story of BRAF

The relapse of melanomas caused by BRAF were once nearly universal but may soon become a thing of the past.

BRAF Mutations at a Glance
  • BRAF mutations are responsible for 66 percent of melanoma cancers, and also drive a rare form of hairy cell leukemia.

  • Finding new BRAF mutations is an active area of research, with BRAF mutations found at lower rates in a variety of other cancers, including gliomas, colorectal cancers, lung cancers, ovarian carcinomas, breast cancers, and liver cancers.

  • When BRAF works properly, it helps cells grow larger and divide at the appropriate time. When mutated, it can send out a signal for cells to divide in perpetuity, leading to cancer.

  • There are BRAF-targeting therapies available, but most cancer develops resistance to these drugs within six to nine months of treatment. Researchers are searching for ways to delay or prevent that relapse.

  • In 2015, researchers identified one reason for this relapse: BRAF inhibitors can promote the growth of another protein called VEGF, which helps the cancer thrive. VEGF inhibitors, originally created for other purposes, are already in clinical trials.

  • Testing for a BRAF mutation requires a tumor sample, ideally taken during a recent biopsy.

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BRAF

This gene is also known as:

B-Raf Proto-Oncogene, Serine/Threonine Kinase

Nearly every person that’s successfully treated for melanoma caused by a BRAF mutation experiences a relapse within six months. It’s such a common occurrence, in fact, that a huge amount of cancer research these days is dedicated to understanding why BRAF melanomas can’t be cured in the first go-around of drug treatment. Since their first development in the 1980s and 1990s, targeted cancer therapies have been a huge breakthrough in pushing closer to a cure. But the relapse of BRAF cancer patients is proving that targeted treatments aren’t enough anymore. A new discovery, announced in March 2015, may have finally found a way to treat the melanoma and eliminate the relapse before it even begins.

If you have a malignant melanoma, chances are it’s caused by a mutation to the gene that codes for the BRAF protein. The mutation accounts for 66 percent of all melanoma cancers. Like many cancer-causing mutations, BRAF is an essential part of the signaling process in your cells that tell them when it’s time to grow larger or divide and make more cells. Small molecules released into your system float around the body and attach to receptors on the surface of your cells. When a molecule fits perfectly into a receptor on a healthy cell, it will trigger a series of signals that are sent into the nucleus of the cell, which tell it to perform a certain behavior. Simply put, the molecule in the receptor tells a bunch of proteins to pass a baton along to the next one in line until the baton gets to the nucleus.

In the case of BRAF, those signals (collectively known as a pathway) tell the nucleus of the cell to grow and divide. But in a cancer cell, the signaling pathway often acts in a way it’s not supposed to. When your BRAF gene is mutated, caused by the simple mistake of DNA switching a single amino acid in building the BRAF protein, the signals telling your cells to grow and divide get wonky. The protein becomes continually active. It sends the grow/divide signal without stopping. It doesn’t need a molecule to trigger it to send the signal and, because of that, there’s no way to tell it to stop. In other words, BRAF just makes its own batons and keeps passing them along in perpetuity.

You can imagine what happens when a signal to grow and divide keeps coming and coming. Your body makes tons and tons of cells. Way more than are necessary in the healthy functioning of your skin’s systems. And a tumor is born. Since the pathway and mutation were first discovered in 2002, scientists have discovered that BRAF mutations cause more than melanoma—they also drive a rare form of hairy cell leukemia. The mutation is such a new advance in the drug-discovery world, where new treatments routinely take 10 to 30 years to develop, that researchers are still finding new types of BRAF-driven tumors all the time. It’s considered a cutting-edge area of cancer science. That said, melanoma is the most common cancer caused by BRAF mutations.

And, in fact, it’s one of the most common cancers in humans. There are nearly 80,000 new cases every year. Two drugs have been released that specifically target the out-of-control signaling of altered BRAF proteins. On the molecular level, the drugs attach to BRAF’s receptor and, basically, turn it off. They tell it to stop signaling and keep quiet. This shushing is incredibly successful, but only for a time. Cancer cells don’t just sit idly by and let an outsider tell its receptors to keep it down. Almost universally, within six to nine months of treatment, the cell develops resistance to the drug, the out-of-control BRAF signaling resumes, and the tumors begin to grow again.

When this universal relapse was first discovered, scientists believed the reasons behind it would easily be found. But as they started digging in, they kept coming across more and more ways that the pathway could be reactivated. One way they’re trying to delay or prevent the relapse is with a second targeted drug that shuts down the MEK protein—that’s the guy that takes the baton from BRAF and hands it over to another protein, which gives it to the nucleus. MEK inhibitors are already used to treat other forms of cancer, so researchers think that using the two drugs (one that shushes BRAF and one that shushes MEK) together might mean the two proteins will have a harder time becoming chatty again.

But in a new discovery announced in March 2015 in the Journal of Clinical Cancer Research, scientists at The Wistar Institute announced they may have found a better way to stop the relapse. Until recently, researchers believed the main cause for the relapse was that the BRAF gene continued to mutate, and the accumulation of those new mutations made the drug stop working. But the new research looked beyond this immunity to the medicines.

“What we identified was a unique way they relapse,” says Dr. Russel E. Kaufman, the lead researcher on the paper. It turns out the drugs themselves seem to be responsible for the relapse. “[The drug] clearly works on BRAF and we discovered that the inhibitor activates a normal cell called macrophages. It has an off-target effect beyond what it’s designed for.”

Macrophages are small blood cells. When they live in tumors, they make the tumors grow faster. That’s because they activate something called the vascular endothelial growth factor, also known as VEGF. Put simply, VEGF allows a tumor to grow blood vessels, which in essence feed the tumor. A tumor with active VEGF will grow bigger and faster than one without it. And it turns out that when the BRAF inhibition drugs tell it to be quiet, they also wake up macrophages and get them to start feeding tumors.

“It has the opposite effect of what you want to achieve,” says Kaufman.

The good news is that, in the same study, Kaufman and his team showed that when you target VEGF and block it from working, it reverses the negative consequences of the BRAF inhibitor. And that means combining a BRAF inhibitor with a VEGF inhibitor could possibly prevent a relapse of the melanoma—though, as mentioned earlier, cancer cells are tricky and there are still lots of other ways BRAF could possibly be reactivating itself. According to Kaufman: “There are many, many papers written now about BRAF. There are about 50 papers a month that are coming out. It’s a very hot area of inquiry. Are there better inhibitors, inhibitors that are more or less specific? No one knows what the answer is.”

Still, there’s a much bigger implication to this discovery beyond the relapse of melanoma cancers. The study shows that targeted cancer drugs might have unintended consequences that no one has previously considered. “Initially people made targeted drugs thinking they’d be specific. We’ve shown that when you produce these targeted drugs, the researchers probably need to look at its effect on normal cells,” Kaufman says.

The good news for melanoma sufferers worried about relapse is that VEGF inhibitors are already in clinical trials, since scientists had already developed them for other purposes. According to Kaufman, it would be easy to pull them off the shelf and test them for use in stopping melanoma relapse. And the problem of targeted therapies hasn’t gone unnoticed, either. “Cancers have evolved a thousand ways of evading the treatment,” Kaufman says. And cancer drug researchers have discovered a thousand ways of fighting back.

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